KR100271750B1 - Estrogen/progestin/antiprogestin method and kit for oral contraception and regulating menses - Google Patents

Abstract

The present invention is directed to methods and kits for achieving menstrual control and, if necessary, contraception with low doses of estrogen and progestin, which may result in breakage bleeding and dosing amenorrhea by periodically causing menstruation using antiprogestin.

Description

[Name of invention]

Estrogen / Progestin / Antiprogestin Methods and Kits for Oral Contraception and Menstrual Control

Detailed description of the invention

[Background of invention]

The present invention provides methods and kits for the use of estrogens or estrogen-progestins in combination with antiprogestins to achieve oral contraception and menstrual control in reproductive mammalian females and / or to reduce unscheduled bleeding in women before, during and after menopause. It is about.

Ovulation suppression in the form of estrogen / progestin combination oral contraceptives has been the most effective way to achieve reversible pharmacological fertility control in women, but side effects associated with prolonged contraception by these methods, especially in the 40-44 year old smoking women group As this is known, there has been an increasing interest in achieving contraception at lower estrogen doses over the years.

Thus, during the 30-year history of estrogen / progestin combination oral contraception, the daily estrogen dose has been slowly downregulated for both the purpose of oral contraception in premenopausal women and the estrogen replacement therapy in postmenopausal women. European Patent Publication No. 0,253,607 discloses as a preferred embodiment tablets containing 1 mg of 17β-estradiol and 0.075 mg of levonorgestrel daily on 23 or 24 (23-16) days for premenopausal women with one cycle for a total of 28 days. After dosing for 5 or 4 (2-5) days is described as having a "no-pill" period or a blank-v (f) period, seeing all references cited therein. It is cited in the specification as a prior art document.

At the same time, the reduced androgen activity remains preferential, although the progestin component is somewhat less. In addition, suitability of these formulations has been shown during various regimes, both single and multiphase. As a result, today's oral contraceptives are safer in terms of the incidence and depth of estrogen-related coagulation disease, as well as the more lipophilic progestin's incremental effect of maintaining high levels of circulating levels of the lipoprotein cholesterol. See Spellacy, WN et al., “Am J Obstet Gynecol”, 1980; 137; 109; Scott, JZ et al., “Fertill Steril” 1978; 30: 141; "J Reprod Med." 1990 by Mishell, DR Jr. et al .; 35 (Suppl. 4): 447-481; "Contemp Obstet Gynecol" 1991 by Speroff L .; 36:65; “Conytaception” 1991 by Mailis GB et al .; 43; 23; And Stamplfer MJ, Willett WC et al., “Am J. Obstet Gynecol” 1990; 163: 285.

This evolution of oral contraceptive formulations has been the fastest in Europe, and in the United States as well. Indeed, cumulative data based on oral contraceptive pills containing only 20-35 μg of estrogen per day is based on the US Department of Food and Drug Adminstration's Fertility and Maternal Health Drugs Advisory Committee ) Was instructed to direct the use of small doses of oral contraceptives for healthy non-smoking women of age (35-50 years) near menopause. See (Michel's (1990) and Speroff's (1991)); U.S. Food and Drug Administration, Advisory Committee on Matenal and Reproductive Health, 1989, Rockerville, Maryland; And JAMA 1985 by Rosenberg L. et al .; See 253: 2965. Japan is currently evaluating the standard of safety and efficacy of oral contraceptives for the first time in anticipation of general use for physicians and patients for about one year.

Given the significant reduction in the daily dose of estrogen-progestin dosing in the form of oral contraceptives, there are two principal issues: (1) maintenance of contraceptive efficiency; And (2) avoidance of incidental erosion in endometrial bleeding control. Even the smallest doses of oral contraceptives on the market currently show contraceptive efficacy slowly, while self-initiating both rupture bleeding (improper flow or staining) or dosing-free amenorrhea during “non-pill” days (expected menstruation). The incidence of overall bleeding control problems increased with decreasing estrogen / progestin dose. See, “Endometrial Bleeding and Steroidal Contraception” by Gray, RH; Diczfalusy E, Fraser RS, Webb FTE (Eds). British Bad: Pittman Press; 1990: 14-19, and “Cotraception” 1982 by Coolbey G. et al .; 26: 229.

[Purpose of invention]

It is an object of the present invention to solve the bleeding control problem associated with reducing the daily doses of estrogen and / or progestin when both estrogen and / or progestin are administered simultaneously in oral contraception and hormone replacement therapy.

Another object of the present invention is to provide a method of achieving contraception with very low estrogen and / or progestin oral dosages in reproductive mammalian females.

Another object is to provide the above method of allowing normal menstruation and controlling its initiation.

Another object is to provide the above method, wherein the dosage is self administered.

Another object is to provide the above method, which does not have side effects associated with conventional or low oral dosages of estrogen-progestin oral contraception or hormone replacement therapy.

Another object is to provide a kit for practicing the method of the present invention.

Another object is to provide a pharmaceutical composition effective for causing menstruation and / or reducing unscheduled bleeding (rupture bleeding, staining) in women in estrogen / progestin oral contraception or estrogen and / or progestin replacement therapy.

Other objects will be apparent to those skilled in the art to which the main invention pertains.

[Summary of invention]

In a methodological aspect, the present invention provides a method of periodically administering an amount of antiprogestin effective to reduce or eliminate breakage bleeding, induce shedding of optionally accumulated endometrial tissue, thereby causing menstruation to mammalian females. Comprising a method of avoiding bleeding problems associated with administering estrogen alone or in combination with progestin, which is low enough to cause breakage bleeding and dosing amenorrhea in mammalian females.

In terms of the article of manufacture, the present invention provides an amount of antiprogestin that causes menstruation, a mixture with estrogen and progestin that is effective to achieve oral contraception when taken daily, without interruption, in a continuously reproducible woman of 20 days or more. A pharmaceutical composition comprising oral administration and estrogen-progestin hormone replacement therapy, which is suitable for oral administration and menstrual induction, is provided.

In terms of other articles of manufacture, the present invention provides for more than 20 days to achieve oral contraception in women in which one dosage unit is reproductive, such as, for example, "Levien 21" by Berlex Laboratories. Regarding kits which are taken daily, but which contain at least 20 oral dosage units each containing a totally effective amount of estrogen and progestin, in promoting the development of breakage bleeding and / or dosing amenorrhea, and arranged in a conventional manner will be.

In a first embodiment of the kit of the invention, an additional oral dosage unit containing only menstrual triggered amount of antiprogestin is arranged to be taken after 20 or more estrogen / progestin oral dosage units have been taken. In a variation of this embodiment of the kit, the number of estrogen / progestin combined oral dosage units preceding the antiprogestin containing oral dosage unit is increased to, for example, 21 or more, for example up to 20 or 180 units. In another variation, progestin is missing in some or all of the tablets for use in estrogen replacement therapy in postmenopausal and postmenopausal women, and antiprogestin significantly reduces or eliminates bleeding bleeding and / or accumulates endometrial tissue It is present in an amount that induces stripping. Such modifications are intended for individuals who wish to extend the length of the medically controlled menstrual cycle beyond the period of four weeks in general.

In a second embodiment of the kit of the invention, the six or more placebo oral dosage units for maintaining a “one fill per day” regimen and reminding an individual when a new dosing cycle should be initiated are described above. Oral dosage units of embodiments, such as “Levien 28” from Berlex Laboratories, are administered to be taken after 20 or more dosage units.

In a third preferred embodiment of the kit, instead of the six or more placebo oral dosage units, the kit contains 28 or 29 or 30 oral dosage units, each of which contains the first 21 doses of the first embodiment, respectively. It contains small doses of estrogen and progestin corresponding to the unit. In this embodiment, the dosage unit arranged to be taken on day 22 also contains a menstrual trigger amount of antiprogestin.

[details]

The present invention provides one month of oral administration of estrogen and progestin daily for about 21 days with an incidence of increased rupture bleeding and stopper amenorrhea, when oral contraception is achieved using less than conventional estrogen and progestin dosages. Use of antiprogestin to help menstruation at any time during the “drug-free” week of the cycle, that is, during the week without estrogen and progestin, or preferably during daily administration of estrogen and / or progestin without interruption. It is based on the finding that it can be minimized or completely avoided by causing it.

In addition, normal menstruation can be achieved using antiprogestin at the same time without interrupting successively low doses of the estrogen / progestin oral contraceptive regimen. Consecutive, very low doses of the estrogen / progestin oral contraceptive regimen in combination with antiprogestins, such as RU 486, at periodic intervals, for example at 30, 60 or 90 days intervals, provide predictable menstrual control.

The physiological basis for this approach is to keep the degree of pharmacological inhibition of the pituitary-ovarian-uterine axis low by an uninterrupted regimen to avoid “follicle deviation”. With the use of low dose oral contraceptives today, active ovarian follicle growth can be initiated more quickly during “no pills” than when using large doses of pills in the past decades. In other words, all increased endogenous estradiol secretion with rapid endometrial hyperplasia is known to be accelerated over a 7-day period of “no-pill” and not only less discontinuous dysmenorrhea, but also breaks during menstruation. Causes less bleeding. Intermittent administration of progesterone antagonists can be achieved without cessation of unfilled uterus during the regimen of oral contraceptives every four weeks or extended intervals, such as every 60, 90, 120, 150, 180 or more intervals. It is intended to ensure shedding of endometrial tissue.

Intermittent administration of antiprogestin for causing menstruation by the present invention, i.e., intermittent administration of at least about 1 month, for example 2 months or 3 months, 4 months or 6 months, can be achieved by conventional follicular levels of endogenous serum estradiol. Maintaining levels above those associated with low doses of estrogen / progestin oral contraception can avoid abnormal bleeding problems, such as rupture bleeding and dosing amenorrhea.

In the normal menstrual cycle, progesterone is produced further from the corpus luteum, which is produced after ovulation. In the contraceptive method of the present invention, progestin is associated with resistance-free estrogen action by being administered with estrogen for at least the end of each control cycle, e.g., the last two weeks of each cycle, to convert the proliferative endometrium to secretory phase. Reduces the risk of uterine cancer However, menstruation consists of the use of antiprogestin alone, whether or not administration of estrogen and / or progestin interrupts menstrual week during the menstrual cycle when administering antiprogestin.

The daily oral dose of estrogen and progestin administered generally is the smallest amount that can achieve a reliable contraceptive or hormone replacement therapy in women, namely about 5-35 mcg of ethynyl estradiol and noethynedrone acetate Contraceptive dose corresponding to 0.5 to 1.5 mg. The daily dose may be equivalent throughout the month, or when both menstruation is desired, such as in the case of “Tri-Levien” by Berrex Laboratories, during both menstrual weeks in the cycle or one of the two If the amount can be reduced or reduced, it can be changed weekly. However, if the dose is eliminated or lowered during menstrual week, it is desirable to increase the dose during the other week of the cycle such that for 2 weeks, especially 3 weeks, no bleeding bleeding occurs before menstruation.

Likewise, when monthly menstruation is undesirable, for example in postmenopausal women, the dose of estrogen and / or progestin may be administered for a long period of base-line, for example in a predetermined period after the last menstruation. A simple, periodic increase in excess of the amount can inhibit breakage bleeding in the short term as a result of low levels of estrogen and / or progestin administration over an extended period of time.

Examples of progestins that can be used in the present invention include micronized progesterone (15-50 mg / 1 day), noethine drone and its esters such as acetate (0.1-0.75 mg / 1 day), noethinodrel (0.3-0.6 mg / day); Ethinodiol diacetate (0.3-0.75 mg / 1 day), norgestrel (0.05-0.2 mg / 1 day) and levo-norgestrel (0.03-0.15 mg / 1 day), chlormadinone acetate, cypro Theron, Cyproterone Acetate, Noethetrone, Desogestrel, Norgestimate, Dihydrospirenone, Levo-Norgestrel, and Gestode (Schering Ag, Berlin, United States Patent No. 4,081,537) (The amount corresponding to 0.03-0.15 mg of levo-norgestril).

A list of these compounds can be found in B. Runnebaum et al. [“Female Contraception: Update and Trends”, Springer-Verlag, Berlin 1988, 64-90, 109-121, 122-128 and 129-140]. This can be found in the paper, which describes compounds active premenstrual. For example, various progestins are described on pages 65 and 68-70, synthetic progestogens are described on pages 110 and 111 (FIG. 1 and Table 1), and FIG. Gestogens are described in Tables 129-133 (Figures 1-10) and Page 137, Table 2 lists progestogens, or US Pat. Nos. 4,681,875 and 4,738,957 for long periods of time. Esters of functional estriols are described.

Examples of estrogens that can be used in the present invention include ethynyl estradiol and estradiol and esters thereof, such as acetates, valerates, benzoates and undecylates (5-15 mcg / 1 day)), mestranol (20-25 mcg / 1 day) and conjugated estrogen (5-15 mcg / 1 day).

Progestins and estrogens can be administered in a conventional manner via any route in which the selected progestins and estrogens are active, for example via oral administration, intramuscular injection, subcutaneous injection or vaginal canal. Most estrogens and synthetic progestins are orally active and are therefore preferably administered by the oral route, for example in the form of tablets, dragees, capsules or pills. If progestin and / or estrogen are administered in tablet or dragee form, dragees may be used in a pharmaceutically acceptable carrier such as a binder such as tragacanth, corn starch or gelatin; Disintegrants such as alginic acid; And lubricants such as magnesium stearate. In addition, estrogens and / or progestins may be delivered transdermally or by route of the vaginal canal.

Since only antiprogestin is effective in inducing menstruation, estrogens and / or progestins are preferably administered uninterrupted, or their administration is during or during menstruation, for example on the first day of antiprogestin And then for about 6 days or less. Thus, estrogens and progestins can be administered uninterrupted at doses lower than the conventional dose for up to 6 months or longer, during which time menstruation is 1, 2 and / or 3 days prior to the desired start of menstruation. Administration of menstrual triggered amounts of antiprogestin can lead to the desired preselected frequency, for example every 20 days, 30 days, 60 days 90 days, 120 days, 150 days or 180 days.

Examples of antiprogestins that may be used in the present invention include RU-486 (“Miferpristone”, Roselle Uclaf, Paris); and “Onapristone” (Schering, Berlin; United States) Patent 4,780,461) and the steroids described in the following patents and patent applications, ie those described in the United States, in particular US Pat. No. 4,609,651, in particular the compound rilopristone (11β- (4-dimethylamino-phenyl-17β-hydroxy-17α- (3- Hydroxy-prop-1- (Z) -enzyl-4,9 (10) estradion-3-one); those described in US patent application Ser. No. 06 / 827,050, in particular compound 11β-4- (acetylphenyl) -l7β-hydroxy-17α- (1-propynyl) -4,9-estradion-3-one and 11β- (4-acetiphenyl) -17β-hydroxy-17α- (3-hydroxy-1 (2) -propenyl) -4,9-estradion-3-one; US patent application Ser. No. 07 / 283,632; US patent application corresponding to EP Patent Publication No. 04042831. US Pat. No. 07 / 541,806; and other antigestation agents, for example, as described in US Pat. No. 4,891,368. Antiprogestin administered in single or divided doses at 24-72 hour intervals. The amount is typically about 50 to 500 mg The minimum amount necessary to induce menstruation at a scheduled time can be readily determined by routine clinical trials.

After administration of antiprogestin, for example in single or divided doses, in the same or continuously, menstruation usually takes place within about 3-4 days thereafter.

Optionally, the antiprogestin may be combined with a daily dose of estrogen and progestin to a suitable day or days in the cycle, such as 20 days or any day thereafter, such as 30 days, 60 days, 90 days, 120 days, And 150 days and / or 180 days.

In terms of embodiments of the article of manufacture, the present invention relates to materials, reagents, and kits for practicing the methods of the present invention.

In terms of kits, the present invention relates to 20 or 28 dosage units suitable for oral administration and to other conventional multi-dose unit manufactured articles. All modifications are effective to block follicle formation for one cycle when their one dosage unit is administered in-house for 21 days continuously, within their first 20 or more generic units, but not so much as to avoid the occurrence of bleeding problems. It contains small amounts of estrogen and progestin. The final dosage unit of the 21 dosage unit variants and the 22nd dosage unit of the 22 and 28 dosage unit variants contain an amount of antiprogestin effective to prevent the occurrence of bleeding problems and cause menstruation. The 22nd to 28th dosage units of the 28 dosage unit variants all contain low doses of estrogen and progestin as well as the first 21 dosage units.

Dosage units containing estrogen and progestin and / or antiprogestin are preferably suitable for oral administration, but may alternatively be suitable for sublingual, rectal, intravaginal or topical (skin application) administration. Suitable units for oral administration are also preferably in the form of tablets, capsules or dragees. It is also preferred that the antiprogestin is contained in the same unit or units containing estrogen and progestin.

In general, pharmaceutical compositions used in the methods of the invention will typically contain antiprogestin in combination with a pharmaceutically acceptable carrier. In general, the effective dosage of antiprogestin is about 1.0 to 10 mg / kg body weight of the host when administered orally. Effective dosage will vary depending upon the mode of administration chosen and the particular species of mammal being treated.

In terms of the detoxifying composition, the present invention contains a menstrual-induced amount of antiprogestin in a mixture with an oral contraceptive dose of oral active estrogen or orally active progestin when taken in reproductive mammalian females for 21 consecutive days, For solid dosage forms, oral dosage forms optionally containing conventional pharmaceutically acceptable carriers such as binders, fillers or diluents such as pills, tablets, caplets or capsules or solutions, or It relates to the aqueous or alcoholic liquid solution described above. This composition is intended to be taken by an estrogen and progestin contraceptive regimen continuously or sequentially to an individual when desiring menstruation, for example by conventional daily combined oral estrogen and progestin doses.

Since the pharmaceutical composition of the present invention may not change over its daily dosage period, oral estrogen / progestin in bulk form, such as a bottle of 30, 60 or 100 tablets or capsules or a bottle of liquid formulation. Can be dispersed.

Without further elaboration, it is believed that one skilled in the art can, using the above description, utilize the present invention to its fullest extent. Accordingly, the specific preferred embodiments below are for illustration only and are not intended to limit the invention in any way.

In the above description and in the examples below, all temperatures are in uncorrected degrees Celsius unless otherwise indicated, and all parts and percentages are in weight.

All publications, patents, and publications cited above and below are hereby incorporated by reference.

EXAMPLE

Example I Primate Intermittent Administration of Antiprogestin During Continuous Microdose Contraception

A 34-year-old mature female rhesus macaque (Macaca mulatta) was selected, which is estimated to have a regular ovulation menstrual cycle (28.7 ± 3.4 days for the month before entering the study). Their natural menstrual period was 3.7 ± 1.6 days. These primates are valuable experimental substitutes for research involving the use of oral contraceptives in humans because of their comprehensive physical similarities with the function of the hypothalamus-pituitary-ovarian uterine axis in women. See, for example, “Fertil Steril” by Hogen, GD. 1982; 38:81; "Contraception" by Danforth DR. 1989; 39: 321; And “Contraception” 1989 by van Uem JFHM et al .; 40: 171.

The average body weight of the monkeys was 5.8 ± 1.6 kg (X ± SEM). They were individually accommodated in a controlled environment (12 hours and feed and 23 ° C.). Their diet was any amount of water and commercial food for primates (purina, St. Louis, MO).

The Eastern Virginia Medical School, through its Animal Care and Use Committee, is the National Institutes of Health's “Guide for Care and Use of Laboratory Animals”, Public Health Service's “Principles for the Care and Use of Laboratory Animals” and the U.S. Department of Agriculture's Amendmentation Regulations of the 1985 Amendment to the Animal Welfare Act.

[research plans]

The study was conducted in two parts: Part I relates to the interval of application of three oral contraceptive treatment cycles, each of which consists of 21 days of oral administration followed by gavage for 7 days of no treatment, It is similar to the conventional regimen of oral contraceptive peel packages. This plan ensures that all individuals (32 monkeys have completed the course) are exposed to the dosing regimen during the initial adjustment period, in which the preceding human data is temporarily more than occurs among those who have used contraceptives for long periods of time. Many breakage bleedings have been shown. Gray (1990); See Coolbay (1982) et al. Nitrogen poison (using a cotton swab applicator with 0.9% saline) and other manual work were performed daily at 7 am to 9 am to detect blood (sporting, adequate flow or excess menstruation were recorded continuously). Blood samples were collected daily under mild ketamine anesthesia (30-50 mg in Morris Plains Parker Davis, N. Battalor, NJ) from the femoral vein only two cycles of treatment, including the preceding week. Serum was collected and frozen (-15 ° C.) until radioscopy analysis of estradiol and progesterone (see Danfoss et al. (1989); van Vem et al. (1989)) By completing before start, it was found that ovulation inhibition was achieved by a very low dose regimen.

In Part II, 30 of these primates were treated in 5 treatment groups, 6 marathon each, namely (1) (21 + 7 day regimen), which continued for 6 months oral contraceptives used in Part I; (2) Treatment continued to be combined with a single oral dose of antiprogestin (RU 486) on days 30, 60, 90, 120, 150 and 180 (no “pill-free” period) daily Group administering estrogen-progestin; (3) Same group as group 2 except that progesterone antagonist is administered only on day 60, 120 and 180, and (4) Same tube as group 2 except that RU 486 is administered only on day 90 and 180 ; And (5) randomly assigned to the group for 180 days of estrogen-progestin continuous daily, but not andiprogestin. As in Part I above, daily monitoring was stopped on day 187 to detect vaginal blood. Femoral blood was collected once weekly to identify potential breakdown ovulation with increased progestin, and serum values above 1.0 ng / ml were considered as indications of ovarian corpus luteum function and possible ovulation. Likewise, these same specimens were analyzed for estradiol levels to monitor the performance of endogenous estrogen biosynthesis. Two monkeys were missing from the performance of the protocol because two monkeys were in group 1 and 3 respectively, one with pidgin and the other with local treatment due to mosquito infection. All of these diseases are not believed to be related to hormonal therapy.

[dosage]

In order to achieve oral contraception at very low doses and to control commercial dosing for less weight (than humans) of these primates under test, 1.2 μg / 1 day of ethynyl estradiol and 0.06 mg / 1 day of noethine drone acetate Oral doses were used. This was accomplished by pulverizing a commercially available pill (“Loestrin 1/20” in a conventional 21-day pack from Morris Plains Parker Davis, NJ) containing 1 mg of noethine drone acetate and 20 μg of ethynyl estradiol per tablet. Is achieved.

In the Part II cycle, except for group 1 and 5 animals, RU 486 (“Mifepristone” by Parisi Rosselukraf) is administered intermittently as a single 50 mg tablet in combination with a regimen of consecutive estrogen-progestin oral contraceptives. It was. Previous studies have shown that this dose of RU 486 replaces natural progesterone from the endometrium, myometrial and cervical receptors, and thus is immediate (generally within 48 hours) of both the accumulating and buccal tissues of the uterus compared to transient menstruation. It was shown to be sufficient to cause complete peeling. (See “Fertil Steril” by Healy DL et al. 1983; 40: 253; Contraception 1989 by Danforth et al. 40: 199). Since the estrogen and progestin components were already combined, progestins were also included during the administration of RU 486.

When the monkey weighs about 6 kg and the woman weighs 60 kg, the daily dose the monkey accepts was about 12 μg ethynyl estradiol and 0.6 mg noethin drone acetate, compared to the human dose. Thus, these very low dose oral contraceptive formulations have shown a 40% reduction in estrogen-progestin exposure compared to one of the smallest doses of combination oral contraceptives available on the market today in the United States and Europe. Considering that when a very low dose regimen was used continuously compared to a conventional 21 + 7 day protocol, the treatment date was 92 days or more, and the treatment reduced the exogenous estrogen-progestin exposure rate by 20% or more. .

Statistical Assessment and Results

Differences between the results of the test group of Study Part I, calculated as mean and standard error, were compared by testing at a significant level of P <0.05 using F statistics.

The two monitored menstrual factors (breaking bleeding and discontinuation (“non-pill”) menstrual period) did not show any significant difference (P> 0.05), but the trend of measurement, namely (1) breaking bleeding rate A particular trend was observed in these 2 and 3 cycles that significantly decreased, and (2) the period when the “no-pill” period was slightly reduced in the period of non-dose menstruation. In other words, the incidence of dosing amenorrhea (monitored by a third menstrual factor) at the time point when dosing menstruation was expected was significantly increased (P <0.05) in three cycles of treatment compared to one cycle. The circulating levels of estradiol and progesterone directly reflected the inhibitory action of estrogen-progestin dosing on the pituitary gonadotropin secretion. Serum estradiol is apparently increased during the “no-pill” period close to the two cycles of treatment, but follicle maturation peaks at approximately 60 pg / ml without treatment and inhibition to approximate 25 pg / ml on day 21. It was concealed by redefining the medication as indicated. Since serum progesterone concentrations are at or near the lower limit of detection of the entire assay, the data firmly indicate that ovulation is almost reliably blocked in all 32 monkeys.

Data derived from Part II of the study were listed by treatment group with a profile of endometrial bleeding for six treatment cycles up to 180 days. The mean (+ SEM) days for break bleeding or menstruation was calculated by dividing the total number of recorded days (per treatment cycle for group 1 or 30 days apart for groups 2-5) with the number of individuals in the group observing. In marking the data, intermittent administration of RU 486 to menstruation (stop dosing bleeding or provoked bleeding at predicted intervals) within a “non-pill” period for group 1 or during successive microdose oral contraception. After (groups 2-4), vaginal bleeding detected within 7 days was entered. Likewise, discontinuation of oral contraceptives or failure to observe vaginal bleeding during the expected menstrual period or immediately following administration of the progesterone antagonist were listed as dosing amenorrhea.

In group 1, the occurrence of breakage bleeding slightly varied from one treatment cycle to six treatment cycles. However, the overall data obtained in Part II showed a progressive 2.4-fold reduction (P <0.05) in the breakage bleeding rate compared to the data obtained in Part I. Statistical significance (P ≦ 0.05) was similarly reached in Part II 3 and 6 treatment cycles compared to Part I 1 treatment cycle.

For groups 2-4 with respect to the intermittent administration of a single dose of RU 486 at 30, 60 or 90 day intervals, statistically comparing the combined data of groups 2-4 against group 1 The overall incidence of breakage bleeding was reduced to 57% (P <0.05). However, group 5 showed a single response to oral contraceptives at successive micro doses. The incidence of breakage bleeding was moderately elevated at the 5 th and significantly increased compared to all other study groups at the 30 th day of the 6 th (P <0.05).

In connection with Phil's discontinuation or RU 486-induced menstruation, microdose oral contraceptives are administered with a traditional 21 + 7 day regimen, with fewer days (P <0.05) of menstruation than in the pretreated spontaneous menstrual cycle. And menstruation after administration of RU 486 lasted longer (3.1 ± 0.8 days, P <0.05). There was no significant difference in bleeding profile between the groups treated with RU 486 (P> 0.05). Finally, primates (Group 5) who received 180 days of very low oral contraceptives without interruption showed longer prolonged menstruation (4.9 ± 3.5 days P <0.05) than the other treatment groups. However, due to the observed individual differences, statistical significance (P> 0.05) could not be obtained from the results obtained in the pretreated cycle.

The incidence of amenorrhea in Part II was markedly reduced when RU 486 was administered intermittently during a continuous oral contraceptive regimen. In fact, some monkeys showed short vaginal bleeding for one or two days, but none of the monkeys did not bleed after RU 486. In contrast, the incidence of amenorrhea in the entire 20 and 30% range (P <0.05) was achieved even when continuous administration of the usual regimen or microdose oral contraceptives of 21 + 7 days.

Part II as a whole, plinth serum progesterone concentrations were maintained below 10 ng / ml except when a level of 1.4 ng / ml was found. Reanalysis of these samples yielding concentrations of 0.26 ng / ml suggests that initial values can be obtained from pseudoanalysis rather than indicating a possible increase in ovarian follicle or corpus luteum activity. At the same time, the overall serum estradiol concentrations for groups 1-5 for each of the 180 day study periods were 37 ± 19, 23 ± 7, 27 ± 7, 22 ± 5, 25 ± 3 and 26 ± 6 pg / ml, and RU Irrespective of 486, there was a significantly lower overall estrogen concentration (P <0.05) during the regimen of continuous microdose oral contraceptives.

The result is a microdose oral contraceptive used sufficiently to contain ovulation, either with a 21-day dosing plus a 7-day “pill-free” period of treatment or without interruption for 180 days. Coincided with However, the occurrence of bleeding problems with broken bleeding or with non-dose amenorrhea during the “non-pill” period is associated with RU 486 estrogen / progestin regardless of whether the treatment regimen is normal 21 + 7 days or prolonged continuous treatment. Increased compared to when used in connection with treatment.

Administration of antiprogestin RU 486 at 30, 60 or 90 day intervals results in two improvements in the bleeding profile. Reduced rupture bleeding in the mid-menstrual period and the incidence of reliable menstruation at the expected time were observed, thereby eliminating abortion amenorrhea. In addition, the overall duration of induced menstruation was slightly longer after administration of RU 486. When using oral contraceptives continuously without RU 486, the incidence of breakage bleeding was determined to increase at the fifth and especially at the fifth 30-day interval. Women treated with the same treatment alone receiving progesterone antagonists at 30, 60 and 90 day intervals had the least (57% or less) in comparison to the results when administered in the usual 21 + 7 days or continuously without antiprogestin. ) He experienced temporary bleeding.

The incidence of breakage bleeding among women who have started taking oral contraceptives is known to be higher in the initial fill dose cycle than in subsequent cycles. It is often believed that the reported observations can reflect both the biological effects of hormonal adjustment on medication as well as the unreliable user adaptability among women who have not taken oral contraceptives. The experimental results in this primate model are in part in line with that opinion, i.e. the initial three to four month treatment period when administering very low doses of oral contraceptives with a typical 21 + 7 day regimen in the occurrence of breakage bleeding. A gradual decrease was observed. Although the absolute frequency of breakage bleedings observed was often less than reported in women, this may be due to the adaptability of the experiment to monkeys and / or other differences with regard to dosage, regimen or species. In addition, these primates were stabilized during the three-cycle treatment of Part I and then separated into Group 5 of Part II to further improve the effect of RU 486 on the bleeding control issues associated with the use of low dose oral contraceptives. Insight can be obtained. Even at 30, 60 or 90 day intervals, RU 486 was not only consistent with significantly less breakage bleeding, but also antiprogestin could cause some bleeding within 72 hours in all cases. Without treatment of intermittent RU 486, the incidence of amenorrhea in the expected bleeding period was increased in both the conventional regimen of 21 + 7 days and in the 180-day continuous treatment alone (group 5). The latter data indicate that continuous oral contraceptive regimens sometimes require endometrial peeling to avoid cumulative bleeding irregularities.

From this data, several possible explanations can be provided for improved bleeding control during the regimen of continuous microdose oral contraceptives and the intermittent RU 486 regimen. For example, serum estradiol concentrations are near 25 pg / ml with little change and during the temporary “follicle avoidance” period when a typical 21 + 7 day regimen is used for treatment of RU 486 in the absence of secretory rupture of estradiol, Pill-free ”period of time in three ways: (1) the manner of restraint by its antimutagenic properties for controlling rapid endometrial proliferation with respect to the endometrium, (2) the estrogen dominance (where noethine drone Acedate: ethynyl estradiol ratio is 50: 1), ignoring excessive amounts of progestin; And (3) may cause accumulation of endometrial tissue and ultimately act in a prolonged continuous oral contraceptive regimen, where a greater breakage bleeding rate may be offset by occasional tissue dislodgement.

The overall results of these primate studies include (1) further reduction in the daily dose of estrogen-progestin oral contraceptives; (2) continuous microdose oral contraceptive regimens when the daily fill interval is extended to 30, 60, and 90 days without interruption, and (3) all related to today's low dose oral contraceptive regimens. It is consistent with the possibility of intermittent administration of antiprogestin readings in combination with a continuous oral contraceptive regimen to reduce menstrual bleeding rates during menstruation and relieve dosing amenorrhea.

Thus, the present invention is useful for increasing the stability, user satisfaction and user adaptability of oral contraceptives, regardless of the contraceptive efficacy. In addition, contraceptive efficacy in women is not sacrificed, and in fact, using a 21-day cycle of peel package, the user can be increased by a continuous estrogen / progestin regimen without having to remember the end-initiation date, Adaptability of menstrual nuances in most patients can be significantly lowered by intermittent administration of antiprogestin, which is why very low doses of estrogen / progestin oral contraceptives are increasingly required for reproductive women from teenagers to menopause. .

Thus, some women want regular stop-menstrual menstruation (13 times a year) every four weeks from their periodic oral contraceptives, while others have fewer menstrual cycles as possible, such as four times a year. By taking a stable and effective product designed to be possible, less frequent menstruation is preferred. The present invention, which uses a combination of low doses of estrogen-progestin pill in a continuous regimen, provides such a product when combined with antiprogestin administered only in prolonged periods when menstruation is desired or when medically indicated.

In addition, discontinuation menstruation in some postmenopausal women using sequential or simultaneous estrogen-progestin therapy is a major cause of user adaptation failure. The therapeutic regimen according to the invention stimulates patients after menopause by escaping endometrial tissue accumulated only a few times per year using progestins and antiprogestins used intermittently, and through cardiovascular integrity and through less frequent menstruation. Consecutive use of estrogen replacement therapy in maintaining hormone replacement therapy that is beneficial for long term maintenance of skeletal maintenance can overcome patient dissatisfaction with the periodic bleeding frequency without compromising safety and efficacy.

In the case of hormone replacement therapy, the adaptability to breakage bleeding in most patients is due to their inhibitory effect on progestin itself on the growth of the endometrium and its antimitotic activity, which can aid the beneficial action on the vascular layer of the endometrium. Due to the intermittent inclusion of antiprogestin. Stopping bleeding after antiprogestin administration may not occur due to loss of endometrial transformation by progestin.

Example II Intermittent Administration of Antiprogestin During Estrogen and Estrogen + Progestin Replacement Therapy

[Primates]

Twenty cynomolgus monkeys (Macaca fascicularis) who had previously undergone ovarian resection were implanted with a single-estradiol containing subcutaneous capsule for 281 days. Estradiol was released from these capsules, resulting in a serum estradiol concentration of about 75 pg / ml. Subcutaneous progesterone capsules were implanted at day 191 and the regimen was up to 281 days. Progesterone was released from this capsule, resulting in a serum progesterone concentration of about 4 ng / ml. This study was conducted at the Animal Research Institute of Eastern Virginia Medical College described in Example I.

[research plans]

The purpose of this study was to evaluate the breakage bleeding before and after onpristone treatment in monkeys undergoing ovarian resection with estrogen and estrogen plus progesterone replacement therapy. Twenty monkeys were assigned to the next four groups. That is, the first group took the onapristone vehicle (saline) at 30 days, 60 days, 90 days, 120 days, 150 days, 180 days, 210 days, 240 days, and 270 days. Group 2 received 3 mg / kg of onnapristone intramuscularly at 30, 60, 90, 120, 150, 180, 210, 240 and 270 days. The third group was treated intramuscularly with 10 mg / kg of onapristone. The fourth group was intramuscularly treated with 30 mg / kg of onapristone. Vaginal disinfection was performed daily from day 1 to day 281. An important parameter for evaluation in this study is the incidence of vaginal bleeding.

[Preliminary Results of Study]

The duration of estradiol treatment increases the breakage bleeding rate in the vehicle treated group (group 1). Onapristone treatment in the second to fourth groups does not cause bleeding, but reduces the occurrence of breakage bleeding. When the combination treatment of estradiol and progestin is initiated, onapristone causes vaginal bleeding.

[Kit Example]

Containing 28 unit doses of conventional tablets suitable for oral administration, each tablet is provided with a kit containing 12 mcg of estrogen ethynyl estradiol and 0.6 mg of progestin noethin drone acetate.

(a) In one embodiment, tablets are typically arranged in an elliptical form of annular or elongated “racetrack” with a label corresponding to the number of days in a week, so that the adaptability of the daily dose regimen can be readily ascertained by the patient. .

An example of such a product can be found in Berex Laboratories' “Levien-28”. Tablets arranged to be taken on or after day 21 contain 500 mg of antiprogestin RU 486 (“Mifepristone” from Rossel Ukraf) in addition to ethynyl estradiol and noethynedrone acetate.

(b) In another embodiment, at least 20, such as 20, 23, 24, 30, 60, 90 or 120 tablets containing only estrogen and progestin or only containing estrogen may be used to provide a container, such as a flat surface. It is loosely packaged in a jar or a container such as a flat metal box as is commonly used to contain aspirin tablets. Tablets containing only antiprogestin or tablets containing a mixture of estrogen and progestin are individually packaged, for example, in an acceptable cavity in a bottle cap or individually in a bubble pack adhesively attached to one side of the bottle or metal box. do. On this tablet package, the physician (or patient) may take menstruation (when the tablet contains both antiprogestin and estrogen and progestin) or other tablets (when the tablet contains only antiprogestin) in addition to menstruation. Margins are provided that can describe the day and month that caused the event. The kit contains the number of tablets needed to provide continuous estrogen / progestin therapy during the January menstrual cycle of a 28, 30, 60, 90 or 120 day period.

(c) The amounts of estrogen and progestin are 35 mcg and 1.5 mg per tablet in the first seven tablets, respectively 30 mcg and 0.8 mg per tablet in the next seven tablets and 20 mg each per tablet in the next seven tablets And 0.6 mg, in the last seven tablets 5 mcg and 0.4 mg per tablet, respectively, and other variations of the kit corresponding to the first embodiment.

(d) Modification of each of the above kits in which noethynedron acetate in the tablet was replaced with 25 mcg of gestoden.

(e) Other variations of each kit above, wherein estrogen is replaced with 20 mcg of mestranol.

(f) Other variations of each kit above where antiprogestin was replaced with 500 mg of onapristone.

The above examples can likewise be successfully repeated by replacing generally or specifically described reactants and / or reaction conditions of the present invention as used in the above examples.

Those skilled in the art can easily identify the main features of the present invention from the above description, and various changes and modifications of the present invention can be applied to various uses and conditions without departing from the spirit and scope of the present invention.

Claims (21)

Although 21 tablets in the kit are collectively effective to achieve continuous oral contraception in reproductive women when taken daily in succession, the breakage of bleeding occurs when the administration of tablets is discontinued during each month cycle to induce menstruation. Contains at least about 20 estrogen- and progestin-containing tablets containing an amount so small that occurrence is unavoidable; A kit comprising a tablet containing an amount of antiprogestin effective to induce menstruation, arranged to be taken after 20 or more estrogen and progestin containing tablets have been taken. The kit of claim 1, wherein the estrogen is ethynyl estradiol, the progestin is noethyne drone acetate, and the antiprogestin is pipepepristone. The kit of claim 1 wherein the estrogen is ethynyl estradiol, the progestin is gestodene and the antiprogestin is onnapristone. Menstruation in women who take contraceptive effective amounts of estrogen and progestin and corresponding amounts of estrogen and progestin daily corresponding to 5 to 35 mcg of ethynyl esradiol and 0.5 to 1.5 mg of noethinediol acetate, respectively, for at least 20 days A pharmaceutical composition in unit dosage form for a solid phase containing an amount of antiprogestin effective to induce. The pharmaceutical composition according to claim 4, which contains 0.5 to 35 mcg of ethynyl estradiol, 0.5 to 35 mg of noethine drone acetate and 50 to 500 mg of mifepristone. The pharmaceutical composition according to claim 4, which contains 0.5 to 35 mcg of ethynyl estradiol, 10 to 15 mg of gestodene and 50 to 500 mg of onapristone. The method of claim 1, wherein the estrogen and its daily dose in each tablet is ethynyl estradiol or estradiol or its ester (5-15 mcg / 1 day), mestradinol (20-25 mcg / 1 day) or Kits with conjugated estrogen (5-15 mcg / 1 day). A kit for hormone replacement therapy or conception control alone or in combination with a progestin dosage unit and an estrogen dosage unit and at least one antiprogestin dosage unit effective to ameliorate uterine bleeding control problems. The kit of claim 8, wherein the antiprogestin unit is for periodic administration. The kit of claim 8, wherein the antiprogestin unit is for continuous administration. 10. The kit of claim 9, wherein there is no progestin unit and hormone replacement therapy is performed. The kit of claim 10, wherein there is no progestin unit and hormone replacement therapy is performed. 10. The kit of claim 9, wherein the kit contains progestin units and hormone replacement therapy is performed. The kit of claim 9 which contains progestin units and in which conception control is performed. A kit for controlling fertility of a female, comprising a progestin dosage unit and one or more antiprogestin dosage units effective for ameliorating the problem of suppressing uterine bleeding. The kit of claim 15, wherein the antiprogestin unit is for periodic administration. The kit of claim 11, wherein the estrogen unit is for continuous administration. The kit of claim 12, wherein the estrogen unit is for continuous administration. The kit of claim 13, wherein the estrogen unit and the progestin unit are for continuous administration. The kit of claim 14, wherein the estrogen unit and the progestin unit are for continuous administration. The kit of claim 16, wherein the progestin unit is for continuous administration.